CN104797252A - Skin wound healing and scar reduction with prostaglandin ep4 agonist combinations - Google Patents

Skin wound healing and scar reduction with prostaglandin ep4 agonist combinations Download PDF

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Publication number
CN104797252A
CN104797252A CN201380053624.3A CN201380053624A CN104797252A CN 104797252 A CN104797252 A CN 104797252A CN 201380053624 A CN201380053624 A CN 201380053624A CN 104797252 A CN104797252 A CN 104797252A
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dexmedetomidine
pharmaceutically acceptable
acceptable salt
noise
amount
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CN104797252B (en
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J·克科宁
M·科尔皮威拉
N·萨伦
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Orion Oyj
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
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Abstract

A combination of a prostaglandin EP4 agonist and an effective amount of : a prostaglandin EP2 agonist, a skin growth factor, a small peptide, a small inhibitory RNA targeting excess chronic inflammation or fibrosis, a cytokine with beneficial anti-inflammatory activity, an adenosine A2a receptor agonist, an anti-oxidant, or a combination thereof, may be used to treat skin wounds or scars.

Description

Alleviate the veterinary methods that noise is detested
Technical field
The present invention relates to veterinary medical field.Specifically, the present invention relates to alleviate animal particularly Canis familiaris L. noise detest method.The method individuality comprised to the described treatment of needs uses Dexmedetomidine (dexmedetomidine) or dexmedetomidine (medetomidine) or its pharmaceutically acceptable salt.
background of invention
It is the FAQs of companion animals particularly Canis familiaris L. that noise is detested.It is to fear that large sound is for typical characteristic, thus Canis familiaris L. attempts to avoid or escape sound.The Canis familiaris L. of known at least 20% suffers from the fear to large noise such as pyrotechnics or thunderstorm.Noise is detested can develop into the excessive fear being called noise phobia.This is fear reaction that is brute, strong and that continue, can be formed in any age and any Canis familiaris L. kind.The symptom that noise detests such as phobia can comprise hide, urinate, defecation, chew, sialism, pant, pace (pacing), shake, shake and bark.But Canis familiaris L. owner seldom ask for help to veterinary, detest to treat noise.This may be due to the following fact: at present without the veterinary medicament that the treatment noise of approval is detested, and not shown be the replacement scheme of certain effective non-medicine.
For the treatment that the noise of companion animals is detested, the therapeutic treatment of document suggestion is usually directed to long-term outbreak (a few week) or causes sedation and/or ataxia or have other shortcomings such as people's abuse potential (abuse potential).But, the owner of most of companion animals and veterinary can more be ready with Drug therapy they suffer from the animal that noise detests, described medicine can not facilitate calmness or ataxia, and described medicine is using 1 hour or be effective in the shorter time.
In addition, the calm symptom detested that itself must not abate the noise.It is known that between the killing period of α-2 agonist induction, animal to sound and especially keeps very responsive to sharp-pointed noise usually.Therefore, although calm, noise reactivity keeps or is even enhanced.
Therefore, there is the demand to the effective non-sedating treatment of medical science that the acute noise of companion animals particularly Canis familiaris L. is detested, described treatment quick acting, and be extremely easy to use, to such an extent as to pet owner can perform.
Dexmedetomidine and racemic modification dexmedetomidine thereof are α-2 adrenoreceptor agonists, are used as tranquilizer and the analgesic of Canis familiaris L. and cat at present.Only commercially available as the Dexmedetomidine of the injection form of hydrochlorate and dexmedetomidine.Dexmedetomidine and dexmedetomidine are labeled as veterinary's tranquilizer at present, and Dexmedetomidine hydrochlorate is 375 μ g/m through the dosage that vein uses 2or the dosage used through intramuscular is 500 μ g/m 2; And dexmedetomidine hydrochlorate is 750 μ g/m through the dosage that vein uses 2or the dosage used through intramuscular is 1000 μ g/m 2.
invention summary
Now, find unexpectedly: by using Dexmedetomidine or dexmedetomidine or its pharmaceutically acceptable salt with the dosage not producing clinical sedation at animal subject, the noise effectively alleviating animal particularly Canis familiaris L. is detested.It has also been found that: Dexmedetomidine or dexmedetomidine or its pharmaceutically acceptable salt can be used through permeable membrane, the permeable membrane gel form particularly used to be suitable for oral mucosa (oromucosal) is used, and use easily, detest to alleviate noise.
Therefore, according to an embodiment of the present invention, the invention provides the method that the noise that alleviates animal particularly Canis familiaris L. is detested, it comprises to its individuality of needs, uses the Dexmedetomidine of effective dose, dexmedetomidine or its pharmaceutically acceptable salt.
According to another embodiment of the present invention, the invention provides alleviate animal particularly Canis familiaris L. noise detest method, when it is included in and does not produce clinical sedation, to needing its individuality, use the Dexmedetomidine of effective dose, dexmedetomidine or its pharmaceutically acceptable salt.
According to another embodiment of the present invention, the invention provides alleviate animal particularly Canis familiaris L. noise detest method, it comprises uses the Dexmedetomidine of effective dose, dexmedetomidine or its pharmaceutically acceptable salt to its individuality of needs, wherein individually keeps its ability of standing and walking and without movement disorder sign.
According to another embodiment of the present invention, the invention provides alleviate animal particularly Canis familiaris L. noise detest method, it comprises uses the Dexmedetomidine of effective dose, dexmedetomidine or its pharmaceutically acceptable salt to its individuality of needs, the wherein on your toes and function completely of subject animal, thus the feed of animal, movement or the ability to irritant reaction are not compromised.
According to another embodiment of the present invention, the invention provides the veterinary medicine compositions of permeable membrane gel form, it comprises as the Dexmedetomidine of active component, dexmedetomidine or its pharmaceutically acceptable salt.
According to another embodiment of the present invention, the invention provides alleviate animal particularly Canis familiaris L. noise detest method, it is included in the mucosa particularly oral mucosa of animal particularly Canis familiaris L., use the compositions of the permeable membrane gel form of effective dose, said composition comprises as the Dexmedetomidine of active component, dexmedetomidine or its pharmaceutically acceptable salt.
According to an embodiment of the present invention, the invention provides and provide external member for animals, it comprises: a) compositions of permeable membrane gel form, and said composition comprises as the Dexmedetomidine of active component, dexmedetomidine or its pharmaceutically acceptable salt; B) for holding the packaging of described compositions; And c) for the mucosa description that particularly applying said compositions is detested to alleviate noise on oral mucosa animal particularly Canis familiaris L..
According to an embodiment of the present invention, by Dexmedetomidine or its pharmaceutically acceptable salt particularly hydrochlorate be used as active component.According to another embodiment of the present invention, by dexmedetomidine or its pharmaceutically acceptable salt particularly hydrochlorate be used as active component.
detailed Description Of The Invention
Term " noise detest " used in literary composition refers to that animal subject passes through the sensitivity increased noise feared and/or phobic response (phobic response) shows, and comprises seriously fear relevant with noise phobia to noise.Noise detest is caused such as but not limited to pyrotechnics, thunderstorm, traffic noise, construction noise and shooting by large sound usually.
Term " clinical sedation " used in literary composition mean when realize do not completely lose, the relaxed state being feature with the depression of the vigilance/alertness reduced and central nervous system function.Animal seems to be motionless and sleep (such as Canis familiaris L. lies on the surface), and reactionless to normal stimulus.The clinical sedation of Canis familiaris L. under research environment can be determined by following: such as posture (recumbency ± difficulty of standing up or can not stand up), cheek sound (jaw tone) (that weaken or very weak), to the reaction (reactionless) of noise and complete the ability needing specific operation that is calm and that suppress.
The present invention relates to and alleviate the animal particularly method detested of Canis familiaris L. noise, it comprises uses the Dexmedetomidine of effective dose, dexmedetomidine or its pharmaceutically acceptable salt to its individuality of needs.Find: Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt, not produce the dosage of clinical sedation in animal subject, are effective to alleviating noise detest.Therefore, the on your toes and function completely of subject animal, thus treatment does not damage the feed of animal, movement or the ability to irritant reaction (such as owner calls Canis familiaris L.).
By Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt such as by intravenous or intramuscular route, the animal subject of suffering from noise and detesting can be applied to.But, preferably active component permeable membrane of the present invention is applied to animal subject, is preferably applied to the oral mucosa (oral transmucosal) of animal.Utilize compositions well-known in the art such as patch, wafer (wafer), membrane, solution or semi-solid combination such as Emulsion or gel, can by active component oral transmucosal delivery.Specifically, preferably with semi-solid combination such as oral transmucosal gel form, Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt are applied to animal subject.
The amount of the active component that suitable selection will be used, with when not having less desirable clinical sedation sign, provides enough effects alleviating noise detest.Therefore, in order to alleviate the noise phobia of animal such as Canis familiaris L., Dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are suitable for producing Dexmedetomidine C maxthe amount of plasma concentration is used, described C maxplasma concentration is about 0.05ng/ml to about 0.8ng/ml, more typically about 0.1ng/ml to about 0.7ng/ml, preferably approximately 0.15ng/ml to about 0.6ng/ml, more preferably about 0.2ng/ml to about 0.5ng/ml such as about 0.3ng/ml to about 0.4ng/ml.Dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are suitable for producing dexmedetomidine C maxthe amount of plasma concentration is used, described C maxplasma concentration is about 0.1ng/ml to about 1.4ng/ml, preferably approximately 0.3ng/ml to about 1.2ng/ml, more preferably about 0.4ng/ml to about 1.0ng/ml such as about 0.5ng/ml to about 0.8ng/ml.
The actual amount of medicine to be administered can be depending on the type of the kind of many factors individuality such as to be treated, age and weight, active component used, route of administration and compositions.
Use the noise alleviating Canis familiaris L. to detest for utilizing oral transmucosal, Dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are suitable for about 10 μ g/m 2to about 200 μ g/m 2amount preferably approximately 20 μ g/m 2to about 180 μ g/m 2, more preferably about 30 μ g/m 2to about 150 μ g/m 2amount use, wherein unit μ g/m 2refer to the square meter body area of the microgram/animal subject of activating agent.Use the noise alleviating Canis familiaris L. to detest for utilizing oral transmucosal, dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are applicable to about 20 μ g/m 2to about 400 μ g/m 2amount, preferably approximately 40 μ g/m 2to about 360 μ g/m 2amount, more preferably about 60 μ g/m 2to about 300 μ g/m 2amount use, wherein unit μ g/m 2with explained above.Utilize according to oral mucosa semi-solid gel of the present invention agent, Dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are preferably with 50 μ g/m 2to 200 μ g/m 2, preferred 70 μ g/m 2to 180 μ g/m 2, more preferably 100 μ g/m 2to 150 μ g/m 2amount use, and dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are with 100 μ g/m 2to 400 μ g/m 2amount, preferably 140 μ g/m 2to 360 μ g/m 2amount, more preferably 200 μ g/m 2to 300 μ g/m 2amount use.
For utilizing intramuscular injection to detest to the noise alleviating Canis familiaris L., Dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are usually with about 1 μ g/m 2to about 40 μ g/m 2amount, preferably approximately 5 μ g/m 2to about 30 μ g/m 2amount such as about 10 μ g/m 2to about 20 μ g/m 2amount use, wherein unit μ g/m 2with explained above.For utilizing intramuscular injection to detest to the noise alleviating Canis familiaris L., dexmedetomidine or its pharmaceutically acceptable salt preferred salt hydrochlorate are applicable to about 2 μ g/m 2to about 80 μ g/m 2amount, preferably approximately 10 μ g/m 2to about 60 μ g/m 2amount such as about 20 μ g/m 2to about 40 μ g/m 2amount use, wherein unit μ g/m 2with explained above.
The body weight of Canis familiaris L. and body surface area conversion table are easily obtain in veterinary's handbook, and this is well known to the skilled person.
Semi-solid combination available in the inventive method can be such as gel, Emulsion, ointment or paste.Preferred compositions is gel or Emulsion form.Gel form is particularly preferred.
By method well-known in the art, prepare semisolid dosage form of the present invention.By being mixed with conventional medicinal diluent conventional in semi-solid preparation and carrier by drug substance, prepare semisolid dosage form of the present invention.
Being particularly suitable for semi-solid veterinary medicine compositions of the present invention is be suitable for the semi-solid gel agent that permeable membrane uses, and it comprises as the Dexmedetomidine of active component or dexmedetomidine or its pharmaceutically acceptable salt.Term " semisolid " means to be flowable mechanical force-physical state under middle pressure at this.Preferably, described compositions is easy to injection, mean its can from for topical formulations well-known routine pipe or easily distribute from needleless injector.Semi-solid combination should be enough thickness, can be held in the oral cavity of animal, but viscosity should not be too high, to such an extent as to described compositions is easily swallowed.Preferably, semisolid material should have about 500mPas to about 200,000mPas, preferably approximately 1000mPas is to about 100,000mPas, and more preferably about 5000mPas is to about 50, the viscosity of 000mPas such as about 8000mPas to about 30,000mPas.According to an embodiment, semisolid material have about 3,000mPas to about 50,000mPas particularly about 5,000mPas such as about 20,000mPas viscosity.
Semi-solid gel agent of the present invention has the denseness can smeared when applied, even and if after having found repeatedly to use, be non-stimulated.Therefore, the present composition is different from the semipermeable membrane composition of the patch of the shortcoming may with potential stimulus mucosa, substrate (matrix), membrane or wafer form.
Gel combination can be applied to any suitable mucosa of animal, comprise oral cavity, nasal cavity, vagina and mucous membrane of rectum.Particularly, described compositions is suitable for administration to the oral mucosa of animal, such as cheek, tongue, Sublingual or gingival mucosa.For Canis familiaris L., it is preferably applied to cheek (buccal) and/or gingival mucosa, from here, active component by the mucosa absorption from oral cavity to circulation, and produce expection pharmacological action.Described gel combination is suitable for utilizing suitable applicator such as syringe etc., uses with a small amount of oral transmucosal.Compositions is held in its application position, not easy-to-swallow.Using of semisolid dosage form is easy, and can be completed by the owner of animal or the unskilled processor used in parenteral drug.Alleviate noise detest effect to start be fast, and usually rise in 30 minutes in time of application in Canis familiaris L. and start.Normally about 120 minutes to the about 300 minutes persistent period of effect.Therefore, when Oral Mucosal Route is particularly useful for acute situations such as thunderstorm and pyrotechnics.
In literary composition, the gel of indication is single-phase semi-solid systems, and it is made up of the organic macromolecule (gellant) being distributed in liquid in the mode existed without obvious border between the macromole of dispersion and liquid.Find: the semipermeable membrane composition for animals of gel form is particularly suitable for the present invention.
Gel structure obtains by utilizing suitable gellant.Select the amount of gellant, thus the gel formed has the required rheological equationm of state.Gel according to the present invention is preferably aqueous gel (hydrogel), and wherein liquid flux comprises water.But aqueous gel preparation also can containing the suitable miscible cosolvent of water.Active component uniform dissolution or be scattered in gel combination.
Preferably, permeable membrane gel according to the present invention contains Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt, gellant, permeable membrane penetration enhancer, the miscible organic cosolvent of water and water.
The concentration of Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt in oral mucosa compositions such as semi-solid gel agent compositions be suitably at every composition weight about 0.001 to about 0.2% (w/w), preferably approximately 0.002 to about 0.1% (w/w), be suitably about 0.005 in about 0.05% (w/w) scope.
The pharmaceutically acceptable salt of Dexmedetomidine and dexmedetomidine is prepared by known method.Suitable salt comprises such as all example hydrochloric acids, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. with mineral acid, and the acid-addition salts formed with organic acid such as acetic acid, propanoic acid, hydroxyacetic acid, acetone acid, oxalic acid etc.Hydrochlorate is preferred salt.
Gellant can be any hydrophilic gel formation polymer suitably.Preferably, gellant is selected from cellulose derivative, polyacrylic acid and polyoxyethylene/polyoxypropylene copolymer.Cellulose derivative and polyacrylic acid are particularly preferred gellant.
Suitable cellulose derivative as gellant comprises cellulose ethers such as hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, methylcellulose, hydroxypropyl emthylcellulose, Cellulose ethyl hydroxypropyl ether, hydroxylated cellulose etc.Preferred cellulose ethers comprises hydroxypropyl cellulose and hydroxyethyl-cellulose.
Suitable polyacrylic as gellant comprises carbomer (so-called CVP Carbopol ETD2050).Carbomer is acrylic acid polyalkenyl polyether cross linked polymer, the polymer that acrylic acid polyallylsucrose or polyallyl pentaerythritol are crosslinked typically.They can such as use trade name carbomer, obtain with different stage.Due to the free carboxy of carbomer polymer, the aqueous dispersion of carbomer is acid.The neutralization of the aqueous dispersion of carbomer polymer causes formation by fluoropolymer resin water soluble salt and spontaneous thickening.
Gel (gel) should enough glue, to such an extent as to can be held in the mouth of animal.But viscosity too highly easily should can not swallow gel to animal.
Usually, provide about 500mPas to about 200,000mPas, preferably approximately 1 to be well-suited for gel, 000mPas is to about 100,000mPas, more preferably about 5,000mPas to about 50,000mPas such as about 8, the amount of the viscosity of 000mPas to about 30,000mPas uses gellant, and described viscosity is at Brookfield Digital Viscometer DV-II, LV-4 (cylinder oblique crank Z (spindle)), the upper measurement of the axle factor 64,12rpm, 25 DEG C.According to an embodiment, by gellant be well-suited for gel provide about 3000mPas to about 50,000mPas, particularly approximately the amount of the viscosity of 5000mPas to about 20,000mPas uses.
By adjusting the amount of gellant and/or the pH by adjustment compositions, obtain described suitable viscosity.This is particularly suitable for gellant when being polyacrylic such as carbomer, because its Dependent Viscosity is in the pH of compositions.
The amount of gellant depends on the character of gellant and required viscosity.Preferably described gel has the denseness that can smear, and it ensures to be easy to use a small amount of gel from oral transmucosal syringe etc.Preferably, gel composition of the present invention is inanimate object attachment component such as elastomer etc.Further, gel composition of the present invention is not preferably film-forming type gel composition.
Usually, in the present composition, the amount of gellant is about 0.3 of every composition weight to about 40% (w/w).When gellant is cellulose derivative, the normally every composition weight of the amount of gellant about 0.5 to about 40% (w/w), more preferably about 1 to about 30% (w/w).When gellant is polyacrylic such as carbomer, the normally every composition weight of the amount of gellant about 0.3 to about 5.0% (w/w), more preferably about 0.5 to about 3.0% (w/w).
When gellant is hydroxypropyl cellulose, it is applicable to about 5 of every composition weight to about 40% (w/w), and preferably approximately the amount of 10 to about 25% (w/w) uses.
The pH of compositions is suitably about 3 to about 9, preferably approximately 4 to about 8, more preferably about 4.5 to about 7, more preferably about 5 to about 7, and in the scope of more preferably about 5.5 to about 6.5 particularly about 5.8 to about 6.2.According to an embodiment, the pH of compositions is in about 6.5 scopes about 5.Available suitable alkali compounds such as sodium hydroxide, fatty amine or tertiary amine or with acid compound such as salt acid for adjusting pH.Gellant is subacidity material typically.
Permeable membrane penetration enhancer is the material that can increase drug osmotic mucosa and enter the speed of blood flow.Suitable permeable membrane penetration enhancer comprise such as surfactant such as anion surfactant as the salt of the fatty acid of 5-30 carbon atom, the sulfate of such as sodium lauryl sulphate and other fatty acids; The alkylamine such as oleyl amine of cationic surfactant such as 8-22 carbon atom; And nonionic surfactant such as polysorbate esters and poloxamer; Aliphatic monobasic alcohol class such as decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, linolenyl alcohol (linolenyl alcohol) and the oleyl alcohol of 8-22 carbon atom; Fatty acid such as oleic acid, stearic acid, linoleic acid, Palmic acid, myristic acid, lauric acid and the capric acid of 5-30 carbon atom, and esters such as ethyl caprilate, isopropyl myristate, methyl laurate, hexa-methylene cetylate (hexamethylene palmitate), glyceryl monolaurate, polypropylene glycol monolaurate and polyethylene glycol monolaurate; TC (Transcutol); Methanol and other quintessence oils; Salicylic acid and derivant thereof; Alkyl methyl sulfoxides class such as decyl methyl sulfoxide and dimethyl sulfoxide (DMSO); Azacycloalkyl-2-the ketone that 1-replaces is such as with 1-dodecylaza ring-heptane-2-ketone that trade mark AZONE sells; Amide-type is octyl group amide, oleamide, hexa-methylene lauramide (hexamethylene lauramide), lauric acid diethyl amide, Polyethylene Glycol 3-lauramide, N, N-diethyl-m-toluamide and crotamiton (crotamiton) such as; And with Dexmedetomidine or dexmedetomidine compatible and there is permeable membrane permeate and promote any other active compound.One or more above-mentioned permeable membrane penetration enhancers can be used.The normally every composition weight of the amount of the permeable membrane penetration enhancer in compositions about 0.1 to about 20% (w/w), preferably approximately 0.2 to about 15% (w/w), more preferably about 0.5 to about 10% (w/w), and this depends on permeable membrane penetration enhancer used.
Preferred permeable membrane penetration enhancer is the fatty acid of 5-30 carbon atom, particularly isopropyl myristate; The fatty acid sulfates of 5-30 carbon, particularly sodium lauryl sulphate; And DMSO.Sodium lauryl sulphate is particularly preferred.
When permeable membrane penetration enhancer is sodium lauryl sulphate, by its with about 0.1 of every composition weight to about 5% (w/w), preferably approximately 0.2 to about 3% (w/w), is suitably that the amount of about 0.5 to about 2% (w/w) uses.
The miscible organic cosolvent of water being suitable for inventive gel agent compositions comprises polyalcohols or glycols such as propylene glycol, butanediol, ethylene glycol, preferred propylene glycol; Or C 2-C 4alkanols is ethanol, isopropyl alcohol, normal propyl alcohol or butanols such as; Or its combination.Preferably non-volatile organic cosolvent, particularly propylene glycol.In compositions, about 5 of the normally every composition weight of the amount of the organic cosolvent that water can fuse to about 50% (w/w), preferably approximately 10 to about 45% (w/w), and more preferably about 15 to about 40% (w/w) such as about 20 to about 35% (w/w).
In gel composition, about 15 of the normally every composition weight of the amount of water to about 90% (w/w), preferably approximately 20 to about 80% (w/w), and more preferably about 30 to about 75% (w/w) such as about 40 to about 70% (w/w).
According to a preferred embodiment, the every composition weight of Oromucosal gel formulation comprises Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt of 0.001 to about 0.2% (w/w), the gellant of 0.3 – 40% (w/w); The permeable membrane penetration enhancer of 0.2 – 15% (w/w); The miscible organic cosolvent of water of 5 – 50% (w/w); With the water of 30 – 80% (w/w).
According to another preferred embodiment, the every composition weight of Oromucosal gel formulation comprises Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt of 0.005 to about 0.1% (w/w), the gellant of 1 – 30% (w/w); The permeable membrane penetration enhancer of 0.5 – 10% (w/w); The miscible organic cosolvent of water of 5 – 50% (w/w); With the water of 40 – 70% (w/w).
According to another preferred embodiment, the every composition weight of Oromucosal gel formulation comprises Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt of 0.005 to about 0.5% (w/w), the hydroxypropyl cellulose of 10 – 25% (w/w); The sodium lauryl sulphate of 0.1 – 5% (w/w); The miscible organic cosolvent of water of 15 – 40% (w/w); With the water of 40 – 70% (w/w).
Gel composition of the present invention optionally also can comprise other conventional excipients of this area as antiseptic and/or antioxidant such as benzyl alcohol, nipagin and propyl parabene, butylated hydroxytoluene or butylated hydroxyanisole (BHA); Sweeting agent; Coloring agent; Correctives; Buffer agent; PH adjusting agent; With solubilizing agent such as glycerol etc.
Preferably by the present composition from prefilled syringe with about 0.05-5ml, more preferably approximately 0.1-2ml, also more preferably approximately the volume oral transmucosal of 0.2-1.5ml such as 0.5ml is applied to animal subject.
The present composition preferably contains toner.Such as, after using, painted gel can easily distinguish with saliva.If gel product is discharged in the mouth of animal, owner can notice the general loss of gel.Any accident easily noticed in product and his contact skin situation is also used by owner.
Compositions can be provided with the form of external member for animals, described external member comprises compositions of the present invention, for holding the packaging of described compositions, and the description that the oral mucosa described compositions being applied to animal particularly Canis familiaris L. is detested to alleviate noise.Preferably, described packaging is the syringe that applicator such as can use the present composition of fixed volume.Syringe is preferably prepared with polymeric material such as HDPE.Suitably, the volume of syringe is about 0.25-6ml, and about 0.5-5ml, is more typically about 1-5ml typically.Such as, compositions of the present invention can be packaged in 1ml, 2ml, 4ml or 5ml HDPE syringe.
Explain the present invention further by the following examples, it is not intended and limit the scope of the invention.
embodiment 1.the Oromucosal gel agent of Dexmedetomidine hydrochlorate
embodiment 2.the Oromucosal gel agent of dexmedetomidine hydrochlorate
By adding propylene glycol, coloring agent, sodium lauryl sulphate and water in a reservoir, the gel preparation of preparation embodiment 1 and 2.Described mixture is stirred, until it is miscible and homogenizing.Mixture is warmed to 50 DEG C.Under agitation, slowly hydroxypropyl cellulose is added.Under mild agitation, gel is cooled to room temperature, and under agitation, adds drug substance.By dripping HCl solution, the pH of compositions is adjusted to 6.0.After leaving standstill, obtain the gel clarified.Gel is packaged in 4mlHDPE syringe.
embodiment 3.
With the Canis familiaris L. that suffer from acute noise detest known to New Year's Eve pyrotechnics, the effect of research Dexmedetomidine Oromucosal gel agent.The Canis familiaris L. of 12 different cultivars accepts the Dexmedetomidine Oromucosal gel agent (group DEX) of embodiment 1, and 12 Canis familiaris L.s accept not containing the Placebo gel agent of Dexmedetomidine.Described research is double blinding.Use 125 μ g/m 2the dosage of Dexmedetomidine, is applied to the cheek/gingival mucosa of every Canis familiaris L. by gel with syringe.If needed (as long as the sign that noise is detested occurs) again, allow repetitive administration 5 times at the most, but between using, have the interval of at least two hours.New Year's Eve, in the family of every Canis familiaris L., carry out described research.Utilize compared with a few years ago, owner evaluates the therapeutic effect to the Canis familiaris L. noise detest sign that pyrotechnics causes, and detects effect (invalid, some effects or respond well).The results are shown in table 1.
Table 1. is compared with a few years ago, and owner evaluates the thorough success of therapeutic effect Canis familiaris L. noise being detested to sign
* thorough success=without in the vigilance/calm sign situation of any reduction, the Canis familiaris L. of scoring " good result "

Claims (10)

1., for the method that the noise alleviating animal particularly Canis familiaris L. is detested, it animal subject comprising Xiang Youqi needs uses the Dexmedetomidine of effective dose, dexmedetomidine or its pharmaceutically acceptable salt.
2. method according to claim 1, wherein Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt oral transmucosal are used.
3. method according to claim 1 and 2, wherein Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt are used by with the form of semi-solid oral mucous membrane gel agent.
4. method according to claim 3, wherein the every composition weight of semi-solid oral mucous membrane gel agent comprises the Dexmedetomidine of 0.001-0.2% (w/w), dexmedetomidine or its pharmaceutically acceptable salt; The gellant of 1 – 40% (w/w); The permeable membrane penetration enhancer of 0.2 – 10% (w/w); The miscible organic cosolvent of water of 5 – 50% (w/w); With the water of 30 – 80% (w/w).
5. according to the method in claim 1-4 described in any one, the wherein C of the Dexmedetomidine of animal subject maxblood plasma value is about 0.05ng/ml to about 0.8ng/ml, preferably approximately 0.15ng/ml to about 0.6ng/ml, more preferably about 0.2ng/ml to about 0.5ng/ml.
6. according to the method in claim 1-4 described in any one, the wherein C of the dexmedetomidine of animal subject maxblood plasma value is about 0.1ng/ml to about 1.4ng/ml, preferably approximately 0.3ng/ml to about 1.2ng/ml, more preferably about 0.4ng/ml to about 1.0ng/ml.
7., according to the method in claim 2-5 described in any one, wherein Dexmedetomidine or its pharmaceutically acceptable salt are with 10 μ g/m 2to 200 μ g/m 2amount, preferably 20 μ g/m 2to 180 μ g/m 2amount, more preferably 30 μ g/m 2to 150 μ g/m 2amount oral transmucosal use.
8., according to the method in claim 2,3,4 or 6 described in any one, wherein dexmedetomidine or its pharmaceutically acceptable salt are with 20 μ g/m 2to 400 μ g/m 2amount, preferably 40 μ g/m 2to 360 μ g/m 2amount, more preferably 60 μ g/m 2to 300 μ g/m 2amount oral transmucosal use.
9. for alleviate animal particularly Canis familiaris L. noise detest compound, it is Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt.
10. Dexmedetomidine, dexmedetomidine or its pharmaceutically acceptable salt for the preparation of alleviate animal particularly Canis familiaris L. noise detest medicine in purposes.
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